Identification and characterization of Hoxa9 binding sites in hematopoietic cells
Identification and characterization of Hoxa9 binding sites in hematopoietic cells
复制标题
DOI：
10.1182/blood-2011-03-341081
复制
发表时间：
2012-01-12
期刊：
影响因子：
20.3
通讯作者：
Hess, Jay L.
中科院分区：
文献类型：
--
作者：
Huang, Yongsheng;Sitwala, Kajal;Hess, Jay L.
簇状同源盒蛋白在发育、造血和白血病中发挥着至关重要的作用，但它们调节的靶点及其作用机制却知之甚少。在这里，我们在全基因组水平上鉴定了 Hoxa9 和 Hox 辅因子 Meis1 的结合位点，并分析了它们相关的表观遗传修饰和转录靶标。 Hoxa9 和 Hox 辅因子 Meis1 在数百个高度进化保守的位点处结合，其中大多数远离转录起始位点。这些位点显示出高水平的组蛋白 H3K4 单甲基化和增强子的 CBP/P300 结合特征。此外，这些位点的子集在瞬时转染测定中显示出增强子活性。许多 Hoxa9 和 Meis1 结合位点也与 PU.1 和其他谱系限制转录因子结合，这些转录因子先前与骨髓增强子的建立有关。条件性 Hoxa9 激活与 CBP/P300 募集、组蛋白乙酰化和原癌基因网络（包括 Erg、Flt3、Lmo2、Myb 和 Sox4）的转录激活相关。总的来说，这项工作表明 Hoxa9 通过与造血和白血病重要基因的增强子相互作用来调节转录。 （血。2012；119(2):388-398）
The clustered homeobox proteins play crucial roles in development, hematopoiesis, and leukemia, yet the targets they regulate and their mechanisms of action are poorly understood. Here, we identified the binding sites for Hoxa9 and the Hox cofactor Meis1 on a genome-wide level and profiled their associated epigenetic modifications and transcriptional targets. Hoxa9 and the Hox cofactor Meis1 cobind at hundreds of highly evolutionarily conserved sites, most of which are distant from transcription start sites. These sites show high levels of histone H3K4 monomethylation and CBP/P300 binding characteristic of enhancers. Furthermore, a subset of these sites shows enhancer activity in transient transfection assays. Many Hoxa9 and Meis1 binding sites are also bound by PU.1 and other lineage-restricted transcription factors previously implicated in establishment of myeloid enhancers. Conditional Hoxa9 activation is associated with CBP/P300 recruitment, histone acetylation, and transcriptional activation of a network of proto-oncogenes, including Erg, Flt3, Lmo2, Myb, and Sox4. Collectively, this work suggests that Hoxa9 regulates transcription by interacting with enhancers of genes important for hematopoiesis and leukemia. (Blood. 2012;119(2):388-398)